The present invention relates to a device for monitoring and/or controlling fluid locomotion, method of manufacturing same, and methods of monitoring and/or controlling locomotion of fluid using same. More particularly, the present invention relates to methods and devices for monitoring and/or controlling dripping of fluid through capillaries, micropipettes, microchannels and the like.
Much industrial and academic effort is presently directed at the development of integrated micro devices or systems combining electrical, mechanical and/or optical/electrooptical components, commonly known as Micro Electro Mechanical Systems (MEMS). MEMS are fabricated using integrated circuit batch processing techniques and can range in size from micrometers to millimeters. These systems can sense, control and actuate on the micro scale, and function individually or in arrays to generate effects on the macro scale. MEMS include numerous applications, such as airbag accelerometers, ink-jet heads, radio frequency micro-switches for wireless communications, micro-gyroscopes, digital micro-mirror displays, pico-satellites and the like.
Whenever mechanics can replace electronics, it provides superior functionality and is not subject to undesirable electronic noise. For example, the classical electronic components of fiber-optic networks are now being replaced with optical MEMS switches that enable the creation of arrays of miniature high capacity switches which can play a critical role in the development of large-scale optical switches in fiber-optic networks.
In the most general form, MEMS consist of mechanical microstructures, microsensors, microactuators and electronics integrated in the same environment (e.g., on a silicon chip). The microfabrication technology enables fabrication of large arrays of devices, which individually perform simple tasks but in combination can accomplish complicated functions. For example, MEMS for guidance, navigation, motion control and high resolution flow visualization can provide experimental evidence about small-scale phenomena and thus verify fundamental principles in the microcosm.
One type of MEMS is a microfluidic device. Microfluidic devices include components such as channels, reservoirs, mixers, pumps, valves, chambers, cavities, reaction chambers, heaters, fluidic interconnects, diffusers, nozzles, and other microfluidic components. These microfluidic components typically have dimensions between a few micrometers and a few hundreds of micrometers. The small dimensions of the components minimize the physical size, the power consumption, the response time and the waste of the entire system. Such systems may provide wearable miniature devices located either outside or inside the human body.
Applications for microfluidic devices include genetic, chemical, biochemical, pharmaceutical, biomedical, chromatography, integrated circuit cooling, ink-jet printing, medical, radiological and environmental applications. The medical applications include diagnostic and patient management such as implanted drug dispensing systems. The environmental applications include detecting hazardous materials or conditions such as air or water pollutants, chemical agents, biological organisms or radiological conditions. The genetic and biochemical applications include testing and/or analysis of DNA, and other macro or smaller molecules, or reactions between such molecules in microfluidic devices, in an approach known as “lab-on-chip.”
Microfluidic devices presently occupy an increasingly significant position in chemical and biochemical sensing, molecular separations, drug delivery and other forefront technologies. In a manner similar to that for microelectronics, microfluidic technologies enable the fabrication of highly integrated devices applicable to high throughput, low volume, automatable chemical and biochemical analyses and syntheses. Common fluids used in microfluidic devices include whole blood samples, bacterial cell suspensions, protein or antibody or nucleic acid solutions and various buffers.
Microfluidic devices can be used to obtain a variety of measurements including molecular diffusion coefficients, fluid viscosity, pH, chemical binding coefficients and enzyme reaction kinetics. Other applications for microfluidic devices include capillary electrophoresis, isoelectric focusing, immunoassays, flow cytometry, sample injection of proteins for analysis via mass spectrometry, sample injection of air or water samples for analysis via flamespectrometry, polymerase chain reaction (PCR) amplification, DNA analysis, cell manipulation, cell separation, cell patterning and chemical gradient formation. Many of these applications have utility for basic research and clinical diagnostics.
The development of miniaturized devices for chemical analysis and for synthesis and fluid manipulation is motivated by the prospects of improved efficiency, reduced cost and enhanced accuracy. Efficient, reliable manufacturing processes are a critical requirement for the cost-effective, high-volume production of devices that are targeted at high-volume, high-throughput test markets. In this respect, microfluidic devices are related to separation of components of a complex mixture for the purpose of analyzing the components individually without interference.
One separation method, particularly useful when the partition coefficients of the components (compounds) are similar, is known as high performance liquid chromatography (HPLC). In this method, the sample is entrained in a mobile phase, continuously flowing from one end of a column to the other. The sample is allowed to interact with a stationary phase bed present in the column in the form of a matrix or beads. As the mobile phase passes through the column, the compounds of the sample equilibrate between the mobile and stationary phases. Depending on the nature of the mobile phase, stationary phase and the components to be partitioned, the interacting time with the stationary phase vary from one component to the other, so that different compounds spend different fractions of time in the column, before arriving to its opposite end. This allows the various compounds in the sample to be physically separated along the column. A detection device detects the components when they elute from the column and measures the time spent in the column. Based on this time and the characteristics of the pulse generated by the detection device, the components are identified. The different components may also be individually collected.
Recently, microfluidic chromatography tubes have been developed. It is appreciated that the integration of such tubes on the same chips together with an efficient dripping and flowing monitor and/or controller is of utmost importance.
In the area of life science, microfluidic devices are used for fabricating microchips, such as DNA chips, protein chips and total analysis systems (also known as lab-on-chip). For example, DNA chips are fabricated on a substrate for which probes with known identity are used to determine complementary binding, thus allowing massive parallel gene expression and gene discovery studies. An experiment with a single DNA microarray can provide researchers information on thousands of genes simultaneously. The use of a microfluidic device in the fabrication process of a microchip facilitates the production of small and high-density spots on the substrate. Since only a small amount of solution is needed to make one chip, the cost of chip production is substantially reduced. In addition, a microfluidic device can created spots in consistent quantities and with uniform configurations, so as to enable highly accurate comparisons between spots.
Droplet microfluidics refers to the set of technologies that are being developed for manipulating very small, substantially uniform, liquid drops, micro- to nano-liters in volume, which are supported on a solid surface, sandwiched between two solid plates or sucked into a solid channel. The manipulations include moving the droplets around, making them coalesce, and breaking them up. These technologies have a promising potential for developing commercially viable droplet-based microfluidic platforms for biotechnology and other applications. The reason is that in pharmaceutical and bioanalysis applications, enormous savings can be realized by reducing the required amounts of expensive reagents to micro- or eventually nano-liter volumes. Moreover, the smaller the length scale over which transport processes (convection, diffusion and reaction) take place, the faster the completion time of the process. As such, the drive toward high-throughput screening and diagnostics requires the concomitant development of associated microfluidic enabling technologies.
Droplet microfluidics may be employed in the area of biochemical and biophysical investigations of single cells. Knowledge of cell activity may also be gained by measuring and recording electrical potential changes occurring within a cell, which changes depend on the type of cells, age of the culture and external conditions such as temperature or chemical environment. Thus, precisely controlling the physical and chemical environment of a cell under study significantly enhances the value of the research. Intracellular and extracellular electrical measurements have application in research studies of nerve cell bodies and tissue culture cells such as smooth muscle, cardiac, and skeletal muscle cells.
There are several major different technologies to measure the electrical activity of cells. Known in the art are techniques which are commonly called “patch clamp recordings” [O. P. Hamill et al., Pfleugers Arch. 391, 85-100, 1981], which have developed into very versatile and precise methods. These techniques allow researchers to observe the functioning of a single ionic channel, while monitoring a neuron's electrical activity in the brain, or allow the monitoring of the change in cell membrane area during a process of secretion, etc. The patch clamp technique provides exquisite resolution for measuring ionic currents in cell membranes, using a glass micropipette having an opening end of the order of 0.1 micron. The micropipette is filled with saline solution and is pressed gently onto the cell membrane, forming a stable physical high resistance electrical seal (in the GigaOhm range) on the cell membrane, commonly termed the Giga-seal. When suction is applied to the micropipette the cell membrane breaks and the cytoplasm and pipette solution start to intermix. Once this mixing is completed, the ionic environment in the cell is similar to the saline filling solution of the micropipette. Ionic currents in the cell membrane are thus indirectly determined by measuring the electrical potential of the solution filling the micropipette.
Another device for measuring the electrical activity of cells is an extracellular electrode, which is a microelectrode being attached to the cell membrane from the extracellular side. The capacitive coupling between the micro-electrode and the cell membrane alter the electrode potential which is used to determine and measure action potentials. As the extracellular electrode is only attached to the cell membrane from the outside, the cell membrane remains intact, and, provided that the appropriate conditions (temperature, pH, etc.) are supplied to the cell culture via an appropriate microfluidic platform, the cells can survive for a prolonged period of time.
In the area of brain research, it is believed that with the advent in microfluidic technology, complicated tasks such as mimicking the signaling of neural synapses on a single chip will become possible, leading to a better understanding of the human brain and neural system. In a typical neural network experiment, a network is composed of about 106 neurons and glial cells, which are grown directly on top of a multi-electrode-array. The multi-electrode-array is a dense arrangement of microelectrodes which are used for parallel recording of the electrical activity of cells in a tissue slice or of cells grown in culture. Neurons, which are loosely placed above a particular microelectrode of the MEA form capacitance coupling with that electrode, hence allowing monitoring and recording of both the electrical activity and the electrical stimulation of the neuron.
Furthermore, efforts are being made to develop dense recording/stimulating microelectrode array probes for building an in-vivo electronic interface to the brain, which can deliver drugs at the cellular level using microfluidic channels. Integrated on each probe is a complete closed-loop fluidic control system, including flow meters, microvalves, and micropumps.
The ability to sense, monitor and/or control locomotion, such as dripping, of fluid through or from a microchannel or a micropipette is one of the fundamental properties required for all the above applications. Unlike dripping faucets, which have been studied extensively, monitoring devices in the micro scale are rather complicated systems, which, despite their ubiquitous application, have received little experimental or theoretical attention. Whereas in dripping faucets drop formation can be monitored, e.g., by ultra-fast video microscopy, equivalent methods for microfluidic applications are presently not known.
There is thus a widely recognized need for, and it would be highly advantageous to have, a method and device for monitoring and controlling fluid locomotion and microfluidic based applications and utilities incorporating same.